Conformational space comparison of GnRH and lGnRH-III using molecular dynamics, cluster analysis and Monte Carlo thermodynamic integration

The conformational space available to GnRH and lGnRH-III was compared using 5.2 ns constant temperature and pressure molecular dynamics simulations with explicit TIP3P solvation and the AMBER v. 5.0 force field. Cluster analysis of both trajectories resulted in two groups of conformations. Results of free energy calculations, in agreement with previous experimental data, indicate that a conformation with a turn from residues 5 through 8 is preferred for GnRH in an aqueous environment. By contrast, a conformation with a helix from residues 2 through 7 with a bend from residues 6 through 10 is preferred for lGnRH-III in an aqueous environment. The side chains of His2 and Trp3 in lGnRH-III occupy different regions of phase space and participate in weakly polar interactions different from those in GnRH. The unique conformational properties of lGnRH-III may account for its specific anti cancer activity.     

Coupling Molecular Dynamics and Deep Learning to Mine Protein Conformational Space

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Conformational analysis and dynamics of mannobiosides and mannotriosides using Monte Carlo/stochastic dynamics simulations

The conformation and dynamics of alpha-(1-->2)-mannobioside, alpha-(1-->6)-mannobioside, and of the trisaccharide alpha-Man-(1-->2)-alpha-Man-(1-->6)-alpha- Man-OMe were studied using Monte Carlo/stochastic dynamics (MC/SD) simulations, the AMBER* force field, and the GB/SA implicit water solvation model. The results are in agreement with available experimental data.     

Monte Carlo Comparison of Multiple Comparison Procedures

Seven procedures of multiple comparisons: Tukey, Scheffé, Bonferroni, Studentized Maximum Modulus, Duncan, Newman-Keuls and F are compared with respect to the probability of the correct decision. Monte Carlo simulation shows that there is no the best procedure. AMS 1985 Subject Classification: 62 J 15.     

Conformational free energy of alkylsilanes by nonequilibrium-pulling Monte Carlo simulation

The stationary phase in supercritical fluid chromatography includes alkylsilanes, bearing typically 18-carbon alkane chains, bonded to silica. The silanes are in contact with supercritical carbon dioxide. Interaction of the stationary phase with analytes from the mobile phase depends on conformation of the silanes, whether they form a collapsed layer between the silica and the carbon dioxide or are extended into the carbon dioxide. Although equilibrium conformation of alkylsilanes can be determined by equilibrium Monte Carlo (MC) simulation, that is hampered by slow relaxation of the chains. An alternative is to pull alkylsilanes from collapsed to extended conformations, then calculate free energy change from the Jarzynski equality. This work compares conformational results from equilibrium MC simulation to free energies from nonequilibrium pulling simulations. Because both equilibrium and nonequilibrium simulations are faster for shorter silanes, this work also compares results from 8-carbon and 18-carbon silanes. Free energies from nonequilibrium pulling predict that alkylsilanes tend to bend over and form a layer between silica and carbon dioxide. Results from equilibrium simulations are qualitatively consistent with results from nonequilibrium pulling. Longer-chain silanes have greater tendency to extend slightly into the carbon dioxide.     

Coexistence Densities of Methane and Propane by Canonical Molecular Dynamics and Gibbs Ensemble Monte Carlo Simulations

We present preliminary canonical molecular dynamics (MD) and Gibbs ensemble Monte Carlo (GEMC) results for the vapour-liquid orthobaric densities of methane and propane. Computational advantages and drawbacks of both simulation methods are discussed and future work is outlined on the application of these techniques to the calculation of transport and interfacial properties. n -Alkanes are described through the TraPPE-UA force field. We study the effect of the truncation of interactions in the Lennard-Jones potential on the accuracy of the orthobaric liquid densities for these inhomogeneous systems along the phase diagram. We observed that a cut-off of at least 5.5 times the Lennard-Jones diameter is needed to obtain accurate results for saturated liquid densities.     

Conformational space exploration of Met- and Leu-enkephalin using the MOLS method, molecular dynamics, and Monte Carlo simulation--a comparative study

We report here a comparative study of the molecular conformational energy landscape generated using the mutually orthogonal Latin squares (MOLS) method, molecular dynamics (MD), and Monte Carlo (MC) simulation. The MOLS method, as described earlier from our laboratory, uses an experimental design technique to rapidly and exhaustively sample the low energy conformations of a molecule. MD and MC simulations have been used to perform similar tasks. In the comparison reported here, the three methods were applied to a pair of neuropeptides, namely Met- and Leu-enkephalin. A set of 1500 conformations of these enkephalins were generated using these methods with CHARMM22 force field, and the resulting samples were analyzed to determine the extent and nature of coverage of the conformational space. The results indicate that the MOLS method samples a larger number of possible conformations and identifies conformations closer to the experimental structures than the MD and MC simulations.     

Conformational Analysis of Neuropeptide Y Segments by CD,NMR Spectroscopy and Restrained Molecular Dynamics

Neuropeptide Y (NPY), a peptide amide comprising 36 residue has been shown to act as a potent vasoconstrictor. In order to shed light on the structural requirements for the biological activities with respect to the different prerequisites for affinity to the NPY receptor subtypes Y₁ and Y₂, in the present study the syntheses and conformational analyses of two C-terminal segments, NPY(18–36) and NPY(13–36), are described. The results obtained by CD measurements, two-dimensional NMR spectros copy and a conformational refinement of the NMR-derived structure by molecular mechanics simulations support the findings of previously published structure –activity relationship studies for biologically active and selective compounds. In particular, the α-helical conformation as well as an appropriate exposure of the side chains of the critical C-terminal dipeptide within NPY(18–36) are in agreement with the prerequisites proposed for Y₂ receptor binding of that segment.     

Conformational Analysis of Tetracycline using Molecular Mechanical and Semiempirical MO-Calculations

A combination of gas phase molecular dynamics and systematic conformational searches with semiempirical MO-theory has been used to identify and characterise the low energy conformations of tetracycline in its neutral non-polar and zwitterionic forms and as the deprotonated zwitteranion. The conformations found have been characterised by cluster- and principal components analyses as belonging to three main groups. These are very similar for the nonpolar and zwitterionic neutral forms of tetracycline, but very different for the anion. The likely consequences of the conformational flexibilty for metal ion complexation by tetracycline are discussed.Electronic Supplementary Material available.     

方差组分估计方法MIVQUE和REML的模拟比较

利用ＭｏｎｔｅＣａｒｌｏ方法,对４种数据结构进行了ＭＩＶＱＵＥ和ＲＥＭＬ两种方差组分估计方法的模拟比较。方差组分估计所用的模型为奶牛育种中常用的公畜模型,它包括场年季固定效应、公牛组固定效应和公牛随机效应。４种数据结构中最大的有１２８４７个观察值,场年季效应和公牛效应水平数分别为７７８和４７,它与北京市目前可利用的奶牛头胎产奶量记录资料相当。最小的数据结构只有２００个观察值,１４８个场年季和２０头公牛。比较指标为估计值的偏差和方差（理论的或根据１０００次重复模拟所得的经验值）。结果表明,对于较大样本的数据结构,两种方法差异很小,它们间的估计值的相关接近于１,偏差小于真值的１％,方差近似相等。对于较小样本的数据结构,ＭＩＶＱＵＥ则明显优于ＲＥＭＬ。本研究还表明,对于ＲＥＭＬ来说,类似数据结构１的样本已能满足其渐近无偏性和有效性的大样本特性。     

Hierarchical Conformational Analysis of Native Lysozyme Based on Sub-Millisecond Molecular Dynamics Simulations

Hierarchical organization of free energy landscape (FEL) for native globular proteins has been widely accepted by the biophysics community. However, FEL of native proteins is usually projected onto one or a few dimensions. Here we generated collectively 0.2 milli-second molecular dynamics simulation trajectories in explicit solvent for hen egg white lysozyme (HEWL), and carried out detailed conformational analysis based on backbone torsional degrees of freedom (DOF). Our results demonstrated that at micro-second and coarser temporal resolutions, FEL of HEWL exhibits hub-like topology with crystal structures occupying the dominant structural ensemble that serves as the hub of conformational transitions. However, at 100ns and finer temporal resolutions, conformational substates of HEWL exhibit network-like topology, crystal structures are associated with kinetic traps that are important but not dominant ensembles. Backbone torsional state transitions on time scales ranging from nanoseconds to beyond microseconds were found to be associated with various types of molecular interactions. Even at nanoseconds temporal resolution, the number of conformational substates that are of statistical significance is quite limited. These observations suggest that detailed analysis of conformational substates at multiple temporal resolutions is both important and feasible. Transition state ensembles among various conformational substates at microsecond temporal resolution were observed to be considerably disordered. Life times of these transition state ensembles are found to be nearly independent of the time scales of the participating torsional DOFs.     

Conformational statistics of pectin substances in solution by a Metropolis Monte Carlo study

Using a Metropolis Monte Carlo algorithm, various average properties of several pectic polysaccharide models were calculated based on the conformational energies for parent disaccharides. The relaxed potential energy surfaces of disaccharides were calculated using the CHARMm force field. Solvent effects were evaluated by calculating a solvation energy for each conformational state by estimating contributions from a cavity formation, and from the electrostatic and dispersion interactions between solvent and solute molecules. The behavior of the mean characteristic ratio, the squared radius of gyration, and the persistence length versus chain length is discussed for various structural models, temperature, and solvent. It is found that the unrefined model of the alternating co-polymer polygalacto-galacturonic acid in vacuum is consistent with the experimentally measured dimension of pectin in salt excess. This model is used to generate computer images of the characteristic conformation of pectin chain.     

Binding of Two Intrinsically Disordered Peptides to a Multi-Specific Protein: A Combined Monte Carlo and Molecular Dynamics Study

The unique ability of intrinsically disordered proteins (IDPs) to fold upon binding to partner molecules makes them functionally well-suited for cellular communication networks. For example, the folding-binding of different IDP sequences onto the same surface of an ordered protein provides a mechanism for signaling in a many-to-one manner. Here, we study the molecular details of this signaling mechanism by applying both Molecular Dynamics and Monte Carlo methods to S100B, a calcium-modulated homodimeric protein, and two of its IDP targets, p53 and TRTK-12. Despite adopting somewhat different conformations in complex with S100B and showing no apparent sequence similarity, the two IDP targets associate in virtually the same manner. As free chains, both target sequences remain flexible and sample their respective bound, natively -helical states to a small extent. Association occurs through an intermediate state in the periphery of the S100B binding pocket, stabilized by nonnative interactions which are either hydrophobic or electrostatic in nature. Our results highlight the importance of overall physical properties of IDP segments, such as net charge or presence of strongly hydrophobic amino acids, for molecular recognition via coupled folding-binding.     

Conformational changes of peptides at solid/liquid interfaces: a Monte Carlo study

Monte Carlo simulations were performed to study the conformational changes of negatively charged model peptides dissolved in water adsorbed onto charged surfaces. 8-, 16-, and 20-residues peptides were used, each of them consisted of repeating diblock units of aspartic acid (ASP, polar amino acid) and isoleucine (ILE, nonpolar amino acid) residues. We found that a water patch was retained at the charged surface, separating the peptide from it. We believed that these water molecules were primarily responsible for giving a particular orientation to the peptide at the surface. Water did play a role to some extent in the structural stability of the 8-residues peptide. However, for higher chain lengths (16-residues and 20-residues), the intrinsic hydrogen-bonding network (or intrinsic structural stability) showed a predominant effect over hydrophobic dehydration for the stability of the peptide at the surface.     

Monte Carlo Study of Structural and Thermodynamic Properties of Liquid Chloroform Using a Five Site Model

A five site potential model combining Lennard–Jones plus Coulomb potential functions has been developed for chloroform molecule. The partial charges needed for Coulombic interactions were derived using the chelpg procedure implemented in the gaussian 92 program. These calculations were performed at the MP2 level with MC-311G* basis set for Cl and 6-311G** for C and H atoms. The parameters for the Lennard–Jones potentials were optimized to reproduce experimental values for the density and enthalpy of vaporization of the pure liquid at 298 K and 1 atm. The statistical mechanics calculations were performed with the Monte Carlo method in the isothermic and isobaric (NpT) ensemble. Besides the values obtained for density, ρ, and molar enthalpy of vaporization at constant pressure, Δ H_V, for liquid chloroform, results for molar volume, V_m, molar heat capacity, C_p, isobaric thermal expansivity, α_p, and isothermal compressibility, κ_T, for this pure liquid are also in very good agreement with experimental observations. Size effects on the values of thermodynamic properties were investigated. The potential model was also tested by computing the free energy for solvating one chloroform molecule into its own liquid at 298 K using a statistical perturbation approach. The result obtained compares well with the experimental value. Site–site pair correlation functions were calculated and are in good accordance with theoretical results available in the literature. Dipole–dipole correlation functions for the present five site model were also calculated at different carbon–carbon distances. These correlations were compared to those obtained using the four site model reported in the literature. An investigation of the solvent dependence of the relative free energy for cis/trans conversion of a hypothetical solute in TIP4P water and chloroform was accomplished. The results show strong interaction of water and chloroform molecules with the gauche conformer. The value obtained for the free energy barrier for cis/trans rotation in TIP4P water is higher than that for chloroform. This result is in agreement with the continuous theory for solvation as the conformer with higher dipole moment is more favoured by the solvent with higher dieletric constant. The results also show an increase in entropy as the solute goes from the cis to the trans geometry and this result is more appreciable in the aqueous solution. This revised version was published online in June 2006 with corrections to the Cover Date.     

Comparison of dosimetric characteristics of physical wedge and enhanced dynamic wedge in inhomogeneous medium using Monte Carlo simulations

BackgroundWidely used physical wedges in clinical radiotherapy lead to beam intensity attenuation as well as the beam hardening effect, which must be considered. Dynamic wedges devised to overcome the physical wedges (PWs) problems result in dosimetry complications due to jaw movement while the beam is on. This study was aimed to investigate the usability of physical wedge data instead of enhanced dynamic wedge due to the enhanced dynamic wedge (EDW) dosimetry measurement hardships of Varian 2100CD in inhomogeneous phantom by Monte Carlo code as a reliable method in radiation dosimetry.Materials and methodsA PW and EDW-equipped-linac head was simulated using BEAMnrc code. DOSXYZnrc was used for three-dimensional dosimetry calculation in the CIRS phantom.ResultsBased on the isodose curves, EDW generated a less scattered as well as lower penumbra width compared to the PW. The depth dose variations of PWs and EDWs were more in soft tissue than the lung tissue. Beam profiles of PW and EDW indicated good coincidence in all points, except for the heel area.ConclusionResults demonstrated that it is possible to apply PW data instead of EDW due to the dosimetry and commissioning hardships caused by EDW in inhomogeneous media.     

Integration of the M6 Cyberknife in the Moderato Monte Carlo platform and prediction of beam parameters using machine learning

PurposeThis work describes the integration of the M6 Cyberknife in the Moderato Monte Carlo platform, and introduces a machine learning method to accelerate the modelling of a linac.MethodsThe MLC-equipped M6 Cyberknife was modelled and integrated in Moderato, our in-house platform offering independent verification of radiotherapy dose distributions. The model was validated by comparing TPS dose distributions with Moderato and by film measurements. Using this model, a machine learning algorithm was trained to find electron beam parameters for other M6 devices, by simulating dose curves with varying spot size and energy. The algorithm was optimized using cross-validation and tested with measurements from other institutions equipped with a M6 Cyberknife.ResultsOptimal agreement in the Monte Carlo model was reached for a monoenergetic electron beam of 6.75 MeV with Gaussian spatial distribution of 2.4 mm FWHM. Clinical plan dose distributions from Moderato agreed within 2% with the TPS, and film measurements confirmed the accuracy of the model. Cross-validation of the prediction algorithm produced mean absolute errors of 0.1 MeV and 0.3 mm for beam energy and spot size respectively. Prediction-based simulated dose curves for other centres agreed within 3% with measurements, except for one device where differences up to 6% were detected.ConclusionsThe M6 Cyberknife was integrated in Moderato and validated through dose re-calculations and film measurements. The prediction algorithm was successfully applied to obtain electron beam parameters for other M6 devices. This method would prove useful to speed up modelling of new machines in Monte Carlo systems.     

Radiation shielding parameters of some antioxidants using Monte Carlo method

In this paper, radiation shielding parameters such as mass attenuation coefficients and half value layer (HVL) of some antioxidants are investigated using MCNPX (version 2.4.0). The validation of the generated MCNPX simulation geometry for antioxidant structures is provided by comparing the results with standard WinXcom data for radiation mass attenuation coefficients of antioxidants. Very good agreement between W?NXCOM and MCNPX was obtained. The results from the validated geometry were used to calculate the shielding parameters of different antioxidants. The radiation attenuation properties of each antioxidant were compared with each other. The results showed that, on average, the highest and the lowest radiation mass attenuation coefficients were observed on hesperidin and delphinidin chloride, respectively. It can be concluded that Monte Carlo simulation is a strong tool and an alternate method where experimental investigations are not possible and a standard simulation setup can be used in further studies for different biological structures. It can also be concluded that the obtained results from this study are very useful for radiology and radiotherapy applications where antioxidants are frequently used.